tbuckley/cabot-search huggingface dataset:
Characterizing telomerase reverse transcriptase (<i>TERT</i>) promoter mutations (mut) across sex, race, and cancer types.
Authors: Talal El Zarif, Marc Machaalani, Rashad Nawfal, Wanling Xie, Toni K. Choueiri, Mark Pomerantz
Journal: Journal of Clinical Oncology (2023)

3122 Background: TERT promoter mut. have been evaluated as a predictive biomarker for patients (pts) receiving immune checkpoint inhibitors. Understanding the prevalence of TERT promoter mut. by sex, race, and cancer type is essential for optimizing its use. Methods: Pts who underwent next-generation sequencing at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center were identified from the AACR Genomics Evidence Neoplasia Information Exchange (GENIE) registry v11.0. Self-reported race and sex data were extracted for ten cancer types with the highest prevalence of TERT promoter mut. The strength of associations with TERT promoter mut. was quantified by Odds ratios (ORs) and two-sided Fisher’s exact tests, along with FDR-adjusted q-values using the Benjamini-Hochberg method. Results: We identified 31,925 pts – 87.6% (27,970) self-identified as White, 7.1% (2,273) Asian, and 5.3% (1,682) Black. TERT promoter mut. were present in 17% (5,470) tumors, including 56% (1,346/2,411) bladder cancers, 43% (966/2,243) melanomas, 41% (395/959) thyroid cancers, and 23% (183/782) head and neck cancers (HNC). TERT promoter mut. were significantly higher in males vs. females in melanoma, cancer of unknown primary (CUP), hepatobiliary (HPB), and thyroid cancers. In contrast, males harbored fewer mut. vs. females with HNC. Interestingly, TERT promoter mut. varied by race. Mut. frequency was significantly higher in White pts with melanoma (44%, n=964/2176) compared to Asian and Black pts (2.9%, n= 2/67) (OR=25.8; 95% CI = 6.9 - 217, p&lt;0.0001). Asian males with HNC (37%, n= 22/60) were enriched for TERT promoter mut. vs. White males (19%, n= 93/489) (OR = 2.5; 95% CI = 1.4 - 4.4; q=0.03). Within HNC tumors, oral cavity (OC) tumors (44.3%, n= 85/192) were associated with higher TERT promoter mut. vs. other HNC subtypes (16.6%, n= 98/590) (OR = 4.4; 95% CI = 3.03 - 6.26; p&lt;0.0001). Asian pts with OC (70%, n=14/20) harbored more mut. vs. White pts with OC (41.4%, n=70/169) (OR = 3.3; 95% CI = 1.2 - 9; p&lt;0.05). Conclusions: Our study demonstrates differences in the distribution of TERT promoter mut. by sex, race, and cancer type. Considering these variations is crucial for future clinical trial design and biomarker studies. [Table: see text]
Tolerability and toxicity profiles of antibody-drug conjugates for the treatment of malignant neoplasms: A meta-analysis of randomized clinical trials.
Authors: Susu Zhou, Toshiki Kuno, Etsuko Miyagi, Jason Dennis Wright, Hisato Takagi, Yukio Suzuki
Journal: Journal of Clinical Oncology (2023)

e15011 Background: Antibody-drug conjugates (ADCs) are attractive targeted agents in anticancer treatment due to their unique mechanism of action and reduced toxicity compared to other anti-cancer drugs. Yet little is still known about the adverse events profiles associated with ADCs. Methods: A systematic review was performed including randomized controlled trials (RCTs) of anticancer treatment that evaluated the efficacy of ADCs. PubMed and EMBASE were systematically searched for studies from January 1990 to December 2022. RCTs that were registered in ClinicalTrials.gov and had final reports of comprehensive adverse events were also included. We included studies for patients with both solid and hematologic tumors. The odds ratios (ORs) of treatment-related symptoms, and hematologic, hepatic, ocular, cardiovascular, renal, and respiratory toxicities for patients treated with ADCs and those without ADCs were examined. A random effects model was developed to estimate the pooled ORs of each adverse event associated with ADC use. Subgroup analyses were also performed based on the cancer type (solid tumors versus hematologic malignancy) and ADC regimen (ADC versus ADC plus chemotherapy). Results: 20 studies involving 10,075 patients (5,745 patients with ADC and 4,330 patients without ADC) were included. Among the included trials, 14 (70.0%) were trials for solid tumors and 6 (30.0%) were trials for hematological tumors. Among the included trials, ADC monotherapy was used in 15 (75.0%) experimental arms, and combination therapy of ADC with any other chemotherapy was used in 7 (35.0%). ADCs were associated with a higher risk for all-grade fatigue (OR 1.25, 95% CI 1.08-1.45), anorexia (OR 1.36, 1.09-1.69), nausea (OR 1.46, 1.09-1.97) and sensory neuropathy (OR 2.18, 1.27-3.76). Patients treated with ADCs had a significantly lower risk of all-grade febrile neutropenia (OR 0.46, 0.22-0.96), leukopenia (OR 0.47, 0.29-0.77), and neutropenia (OR 0.56, 0.31-1.01). Whereas, they had a higher risk of all-grade increased alanine aminotransferase (OR 2.51, 1.84-3.40), increased aspartate aminotransferase (OR 2.83, 2.04-3.93), cataract (OR 4.69, 1.86-11.81), blurry vision (OR 3.12, 1.02-9.55), pericardial effusion (OR 4.27, 2.71-6.72), and epistaxis (OR 2.45, 1.50-4.01). In the subgroup analysis, a similar toxicity profile was observed when comparing the solid tumors versus hematologic malignancy groups and the ADC versus ADC plus chemotherapy groups, except for hematologic adverse events, which showed an increased risk in patients with solid tumors and those treated with both chemotherapy and ADCs. Conclusions: This comprehensive profile of adverse events associated with ADC-based treatment shows increased treatment-related symptoms, hepatic, ocular, and cardiovascular toxicities although no increase of high-grade are seen.
Real-world data on survival outcomes and characteristics of lung cancer patients in northern serbia.
Authors: Darijo Bokan, Bojan Zaric, Tomi Kovacevic, Goran Stojanovic, Jelena Djekic Malbasa
Journal: Journal of Clinical Oncology (2023)

e22528 Background: Serbia is the one of the countries with the highest incidence and mortality of lung cancer in Europe and survival rates are very low. Despite that fact, there is no recent data published on the incidence, mortality, survival time or the most significant patient characteristics for the Northern Serbian Province of Vojvodina. Methods: For the purpose of this retrospective study data for the period 2010 to 2022 were collected from Institute for Pulmonary Diseases of Vojvodina Hospital Information System and the Lung Cancer Registry. Also, we collected data from seven Public Health Institutes, one for each district to analyze incidence and mortality rates. The primary objective of the study was to determine the impact of demographic and clinical pathological characteristics of patients on overall survival. The secondary objective was to analyze the incidence and mortality of lung cancer in the region of Vojvodina. Incidence and mortality rates were directly age-standardized to the World and Europe Standard Population. Results: A total of 15072 patients were eligible for the analysis, 10413 (69.1%) males and 4659 (30.9%) females. The most of the patients were current smokers (62.9% males vs 63.3% females), stage IV (47.7% males vs 46.9% females), ECOG performance status 1 (78.5% males vs 79.0% females). One-year survival rate for the patients with stage IV squamous carcinoma was 20.5% males vs 27.2% females, adenocarcinoma 18.0% males vs 22.9% females and small-cell carcinoma 10.6% males vs 17.8% females. Three-year survival rate for all stages of squamous carcinoma was 12.7%, adenocarcinoma 11.8% and small-cell carcinoma 2.9%. Five-year survival rate for all stages of squamous carcinoma was 7.4%, adenocarcinoma 6.8% and small-cell carcinoma 1.9%. There was statistically significant difference in survival time by gender in subtypes of adenocarcinoma (p = 0.000), squamous cell carcinoma (p = 0.000) and small-cell carcinoma (p = 0.001). Analysis showed significant difference in survival by age (p = 0.000), cancer type (p = 0.000), stage of the disease (p = 0.000), ECOG performance status (p = 0.000) and smoking status (p = 0.001). Incidence (ASR-W) was 65.4/100000 for males and 21.7/100000 for females. Mortality (ASR-W) was 67.8/100000 for males and 20.9/100000 for females. Conclusions: Northern Serbian Province of Vojvodina is one of the regions with the highest incidence and mortality of lung cancer and overall survival is low. Determining the impact of the most important demographic and tumor characteristics on lung cancer patients’ survival, as well as incidence and mortality rates define the parameters necessary for adequate planning of activities and strategies for improving the prevention, diagnosis and treatment of patients in Vojvodina.
MicroOrganoSpheres as a clinically applicable precision oncology platform for the discovery of novel therapies in colorectal cancer.
Authors: Divya Lakshmi Dayanidhi, Gabrielle Rupprecht, Wylie Watlington, John Mantyh, So Young Kim, Shannon J. McCall, Jason A. Somarelli, Shiaowen David Hsu
Journal: Journal of Clinical Oncology (2023)

3592 Background: Patient-derived models of cancer, such as cell lines, patient-derived organoids, and patient-derived xenografts, are useful models of patient response in the clinic. However, these models are often not clinically applicable within the time periods necessary to inform clinical decision making, as they can take weeks to months to develop. An ideal platform using patient-derived models would be generated from a core biopsy with a subsequent drug screen within 10-14 days to minimize delay in therapy. We recently reported the development of MicroOrganoSpheres (MOS) that can be used in drug screens within 14 days of obtaining a biopsy. In the current study, we use this MOS system as precision oncology platform in colorectal cancer (CRC) to identify new therapies and predict response to therapy. Methods: CRC patient tissue samples were collected under a Duke Institutional Review Board approved protocol (Pro00089222). Resections or biopsies were mechanically and enzymatically digested to obtain a single cell suspension. Cells were then plated in Matrigel at a ratio of 20,000 cells:5 µL Matrigel to establish “mini-bulk” organoid cultures. After establishment for 5-7 days, cultures were harvested with subsequent generation of MOS at a ratio of 50 cells per MOS. After growing for 3-4 days, MOS were used for dose-response curves using oxaliplatin, SN38, and 5-Fluorouracil (5-FU) as well as high-throughput drug screens with the NCI Approved Oncology Drugs Set VI library. Results: We developed and optimized a MOS pipeline on over 50 CRC specimens, including 9 primary rectal, 35 primary CRC, 12 CRC liver metastasis, and 1 CRC lung metastasis lines with a success rate of 80% and an average of 10-21days from biopsy to MOS generation. The high success of generating CRC MOS in a clinically applicable time frame led to the next phase of the project where a total of 10 CRC MOS were tested against standard of care chemotherapy agents used in CRC (oxaliplatin, irinotecan and 5-FU) as well as the NCI Approved Oncology Drugs Set VI within 14-21days of establishment. We noted a range of sensitivity of approximately 100-fold for standard of care agents. The most sensitive drugs found in the high-throughput screen were Bortezomib, Carfilzomib, and Panobinostat and the most resistant were Gefitinib, Chlorambucil, and Procarbazine hydrochloride. Conclusions: These results demonstrate that our MOS pipeline can be used as a precision oncology platform within a clinically applicable time frame to potentially guide therapy. We are now in the process of correlating drug response in MOS to patient outcome data and these findings will be presented at the annual meeting.
The prognostic value of metastasectomy among patients with gastric, pancreatic, and colorectal cancer accompanied by isolated liver metastasis: A SEER analysis.
Authors: Suhib Fahmawi, Usama Abu heija, Ali Abdelhay, Abdallah Al-Ani, Sukesh Manthri
Journal: Journal of Clinical Oncology (2023)

e16026 Background: It is well acknowledged that the poor prognosis of gastrointestinal (GI) cancer is largely due to distant metastasis. It’s been reported previously that metastasectomy, particularly with liver metastasis in colorectal cancer patients, have survival benefit. Multidisciplinary management of distant metastatic cancer mandates the consideration of all treatment options, and in selected patients with hepatic metastasectomy can be performed with curative intent. There is no consensus on the ideal management strategy for synchronous disease. The purpose of this study was to analyze the prognostic value of metastasectomy in patients with certain GI cancers associated with isolated liver metastasis. Methods: A total of 14,204 patients who underwent primary site resection along with metastasectomy for isolated liver metastases from gastric, pancreatic, and colorectal were extracted from the Surveillance, Epidemiology, and End Results database between 2010 and 2019. Patients younger than 18 years, and cases with missing information including age, gender, race, unknown stage, and unknown metastasis site were excluded. Cox-regression analysis estimated the prognostic value of metastasectomy, presented by hazard ratios (HR), among different GI cancers. Survival ratios were controlled for age, race, and gender. All analyses were performed on STATA v17. Results: Study sample included 3% of patients with gastric cancer, 4.2% with pancreatic cancer, and 92.8% were colorectal cancer patients. Incidence of metastasectomy was 19.9% among gastric cancer, 30.69% of pancreatic cancer and 25.76% of colorectal cancer patients. Cox-regression analysis demonstrated survival benefit for patients with gastric (HR 0.65, CI 0.45 - 0.94, p = 0.02), pancreatic (HR 0.51, CI 0.39 – 0.67, p &lt; 0.001), and colorectal cancer (HR 0.58, CI 0.55 – 0.62, p &lt; 0.001) patients undergoing metastasectomy. Conclusions: Aggressive approach with primary site resection along with metastasectomy for isolated liver metastases from gastric, pancreatic, and colorectal cancers significantly improved survival. Prospective data from evidence-based protocols is missing, and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team. [Table: see text]
Efficacy and safety of second-line treatment for advanced gastric cancer: A network meta-analysis of randomized controlled trials.
Authors: Xiaoting Ma, Lin Yang
Journal: Journal of Clinical Oncology (2023)

e16018 Background: To evaluate the difference of curative effect between different treatment regimens in patients with advanced gastric cancer (AGC) who have previously received fluorouracil based first-line chemotherapy. Methods: We searched PubMed, PMC and EMBASE databases for published randomized controlled trials (RCTs). The number of people who reached the objective response rate (ORR) and the hazard ratio (HR) and its 95% confidence interval (CI) of progression-free survival (PFS) and overall survival (OS) were extracted. R (version 4.0.5) and R Studio were used to conduct meta-analysis of relevant data based on the Bayesian framework. Gemtc software package facilitates statistical analysis. To provide a ranking for each treatment regimen, surface under the cumulative ranking curve (SUCRA) was calculated. Survival analysis was conducted based on WinBUGS 14. STATA17.0 was used to draw the network diagram and funnel plot. Results: A total of 17 RCTs were included in this meta-analysis, and a total of 15 treatment regimens were used in the second-line treatment of AGC. There was no publication bias or other bias in the studies. Ramucirumab combined with paclitaxel and nab-paclitaxel weekly regimens have obvious advantages in efficacy and safety. Among them, ramucirumab combined with paclitaxel (83.6%) has great advantages in ORR, while the probability of anemia (36.6%) and anorexia (22.7%) is low, and the probability of leucopenia (66.6%) is high. However, the ORR of nab-paclitaxel weekly regimen (71.4%) is only second to that of ramucirumab combined with paclitaxel, and the probability of anemia (46.3%) and anorexia (44%) is also low, and the probability of leucopenia (53.8%) is high. In terms of OS and PFS, ramucirumab combined with paclitaxel has the best effect according to the probabilistic settlement table. Pembrolizumab and 5-Fu have poor therapeutic effects in terms of PFS. Conclusions: Ramucirumab combined with paclitaxel and nab-paclitaxel can significantly improve the survival outcome of patients with AGC. The effect of ramucirumab combined with paclitaxel is significantly better than that of paclitaxel, and the effect of nab-paclitaxel is only second to that of ramucirumab combined with paclitaxel. The safety of multi-drug combination should also be carefully considered. These findings may help clinicians better choose the second-line treatment strategy for patients with AGC.
PUF: A potential repressor of oncogenes.
Authors: Hafiz Aslam, Mahvish Muzaffar, Myon Hee Lee
Journal: Journal of Clinical Oncology (2023)

e15095 Background: RNA-binding proteins (RBPs) play a crucial role in orchestrating the function of RNAs. The regulation of RBPs is critical in various biological processes, including tumorigenesis. The PUF (Pumilio/FBF) RBPs are of particular interest due to their function in stem cells and tumor-initiating cells. Its has been shown that PUF proteins inhibit the translation of target genes by binding to a regulatory element (PBE) in the 3’ untranslated regions (3’UTRs) of their target mRNA. PUF proteins are required to maintain normal stem cells and potentially inhibit the formation of tumor-initiating cells by repressing the expression of oncogenes. Bioinformatics analysis has identified many oncogenes as potential targets of PUF, and pilot studies have confirmed that ERK, p38, JAK2, RUNX2, and RET mRNAs specifically interact with PUF protein. The objective of this study is to investigate the function of human PUF proteins in the initiation and progression of cancer cells. Methods: In worms (C. elegans), 100 % PUF mutants form tumors. Bioinformatics were performed to identify PUF target genes, it specifically binds UGUAnAUA sequences on target mRNA 3'UTRs. Yeast three-hybrid assay were performed to test the physical interaction between PUF protein and its target mRNA. The novel function of human PUF proteins in the initiation and progression of cancer cells was investigated using CRISPR/Cas9 knockout cancer cell lines and western Blot/IHC was done to determine their expression. Results: The results of the study showed that PUF proteins play a crucial role in inhibiting the formation of tumor-initiating cells. Loss of PUF function and activation of ERK signaling were found to promote the formation of these cells. Bioinformatics analysis revealed that many oncogenes are potential targets for PUF repression. The study also demonstrated that PUF represses the expression of ERK and p38 mRNAs via their 3’UTRs. These findings suggest that PUF may have therapeutic potential as a target for cancer treatment. Conclusions: In worms and human cells, normal PUF proteins promote the cell proliferation of stem cells, however, stem cells begin to differentiate, PUF proteins are required to complete differentiation. Therefore, in the differentiating cells, PUF mutation cannot complete differentiation, instead, return to undifferentiating cells, resulting in tumors. Bioinformatics and biochemical analyses revealed that many PUF repressing targets (~ &gt; 30%) are oncogene and some labs including us found that PUF knockdown enhanced oncogene expression. PUF can be a potential biomarker, as low PUF expression may initiate tumors. Therapeutically, conditional PUF expression in tumor-initiating cells may suppress tumor progression by suppressing oncogene.
HPV integration as a prognostic biomarker for metastatic anal cancer: A next-generation sequencing ctDNA-based approach.
Authors: Benny Johnson, Helene Pelicano, Ryan W Huey, Robert A. Wolff, Ignacio Ivan Wistuba, Dzifa Yawa Duose, Saradhi Mallampati, Rajyalakshmi Luthra, Van K. Morris
Journal: Journal of Clinical Oncology (2023)

3525 Background: Anal cancer is an HPV-associated malignancy with increasing prevalence in the United States. Immune checkpoint blockade demonstrates limited efficacy in patients with metastatic squamous cell cancer of the anal canal (mSCCA), and no prognostic or predictive biomarkers have demonstrated clinical utility in this population. Available circulating tumor DNA (ctDNA) assays have utilized ddPCR methodologies to report only the most common HPV types (HPV-16 and HPV-18) and HPV copy numbers. To extend the utility of an HPV ctDNA assay, we created a novel next-generation sequencing HPV ctDNA assay to analyze HPV integration as a prognostic biomarker for patients with mSCCA. Methods: Using an IRB-approved protocol, ctDNA isolated from the plasma of patients with mSCCA was sequenced using a 1.4Mb hybrid-capture target-enrichment panel covering the whole genome sequences of all 193 HPV types. HPV type, HPV copy number, and HPV integration status/locus were determined using a bioinformatic pipeline developed in-house. A Fisher's exact test was used to compare radiographic and ctDNA changes in response to systemic treatment. Unpaired t-tests were used to compare demographics between patients with HPV integration (I) or no integration (NI) status in the ctDNA. Median survival was estimated (Kaplan Meier) and compared according to integration status using a log-rank test. Results: 68 plasma samples from 27 patients with mSCCA were analyzed. While HPV-16 was detected in ctDNA of all 27 patients, five patients had additional oncogenic HPV types [HPV-18 (2), HPV-45 (2), HPV-73 (1)]. Radiographic changes in metastatic disease volume were concordant with HPV copy number changes in the ctDNA (odds ratio 12.2, 95% confidence interval (CI) 2.0-75; p = .007). HPV integration events were detected in the ctDNA for 16 (59%) patients (median 2, range 1-7 unique events per patient). For the 23 patients with mSCCA who received anti-PD1 immunotherapy (15 I, 8 NI), there were no differences in age (60 vs 59 years, p = .88) or prior lines of treatment (3.0 vs 3.5, p = .72). There was a trend towards improved median progression-free survival for NI ctDNA status (5.8 vs 3.2 months, hazard ratio (HR) 1.8, 95% CI .71-4.5). Relative to NI status, I status was associated with worse overall survival rates (OS) (22.5 vs 44.9 months, HR 5.0, 95% CI 1.5-17, p = .005). Conclusions: Detection of HPV integration status for all HPV types is feasible using a ctDNA-based approach for patients with SCCA. HPV integration was prognostic for worse OS in patients with mSCCA. Identification of HPV integration as a novel prognostic biomarker for survival outcomes in mSCCA warrants further evaluation in larger clinical trials.